One of the most frequently utilized methods to extend the duration of drug action in the body is by modification of the pharmaceutical dosage form. This is usually achieved with single or multicomponent matrix systems such as granules, pellets, tablets or a combination of the above where the drug delivery is mainly controlled by diffusion or erosion mechanisms.
Another commonly used procedure to sustain or control the rate of drug release is by utilizing polymer coating technology. Polymers with pH dependent or independent properties are coated onto the different dosage forms utilizing fluid bed or conventional coating equipment.
The delivery systems described above, traditionally have been used to manufacture many of the available pharmaceutical dosage forms in the market. However, for drugs that present a low melting point or are metastable at room temperature the only available solid oral unit dosage form has been the soft gelatin capsule.
Soft gelatin encapsulation is rather a complex process and usually requires the services of an outside contractor. However, many pharmaceutical companies would prefer to keep development activities in-house for reasons of confidentiality and control over the development process. With the new advances in pharmaceutical equipment technology it is now possible to formulate drug substances into semi-solid, liquid or paste-like form for filling into hard-shell two piece capsules. This type of formulation technology demonstrates an alternative for the difficult to manufacture soft gelatin technology and the ability to maintain the development activities in-house.
There are several advantages that can be obtained by formulating drugs in liquids and/or semisolid (molten) formulations to be filled into hard shell two piece capsules. These are the ability to formulate with low melting point materials, low-dosed or highly potent drugs, compounds that are oxygen- or moisture sensitive, and for drugs that require bioavailability enhancement.
Many of the liquid formulations in hard-shell capsules provide an immediate or fast release. This is usually achieved as a result of the immediate release of the contents due to the fast disintegration time of the gelatin at body temperature. Other formulations utilize sustained release liquid-filled release capsules utilizing thermosoftening matrices. The excipients most frequently utilized are the Gelucires(copyright), Gattefosse(copyright), France, since they are available as semisolids with a wide range of melting points and HLB values. This variety allows flexibility in mixing, adequate filling viscosity, different degrees of bioavailability enhancement and a sustained drug release from the semisolid matrix.
High melting glycerides have frequently been used as lubricants when formulating tablets or capsules. Lubricants have a great effect on the aspect of the finished product and the ejection of the tablet out of the die is improved. Lubricants are usually hydrophobic substances and when used in high amount can alter the desegregation time of the tablet thus delaying the bioavailability of the active ingredient.
The incorporation of lubricants (waxes, HMG) into tablet matrices has been a popular method to prolong drug release. For example, sustained release acetaminophen tablets with glyceryl behenate, Klucel HXF, hydroxy propyl cellulose (HPC), a swellable water-soluble polymer, and Carbopol(copyright) 934, a crosslinked polymer, has been prepared. It was observed that all tablets containing a sustained release agent exhibited some degree of prolonged drug release in vivo as compared to regular tablets. It was also noted that from all sustained release agents evaluated, glyceryl behenate provided the slowest release.
Glyceryl behenate as a potential controlled release wax matrix in spheres and tablets has been evaluated (10, 30 and 50%). At the 10% level no sustained action was observed. However, as the levels of glyceryl behenate increased a significant slower release of the drug was obtained. The results indicated that glyceryl behenate exhibited the potential to create a controlled release matrix.
Sustained release preparations have also been achieved from other high melting glycerides (glycerol palmitostearate and glyceryl monostearate). For example the release of theophylline embedded in a glycerol palmitostearate matrix containing varying amounts of mannitol and/or hydroxypropyl methyl cellulose 4000 (HPMC) was evaluated. The release of theophylline was modulated by varying the fraction of HPMC and/or mannitol used. When both HPMC and mannitol were used the matrix system developed followed a first-order dissolution release.
In general, natural, synthetic and/or semi-synthetic polymers such as cellulose or acrylics derivatives, have been used in high quantities ( greater than 10%) to retard the release of many pharmaceutical active ingredients. Such polymers are not usually recommended to be utilized in small quantities to retard the release of API.
A controlled release pharmaceutical formulation is disclosed. The formulation comprises a matrix construct of a component selected from a high melting point fatty acid ester, an oil, a polymeric cellulose derivative, and a mixture of any of the foregoing, having a selected medicament associated therewith.